Co-crystal of tramadol-celecoxib: preclinical and clinical evaluation of a novel analgesic

ABSTRACT

Introduction: Pain management is a major unmet need due to the suboptimal efficacy and undesirable side effects of current analgesics. Multimodal therapies recruiting complementary mechanisms of action may help address this. Co-crystals incorporating two active pharmaceutical ingredients (APIs) constitute an innovative approach to multimodal therapy, particularly if modification of the physicochemical properties of constituent APIs can be translated into clinical benefits.

Areas covered: The preclinical and clinical profiles of Co-Crystal of Tramadol-Celecoxib (CTC), a novel API–API co-crystal (1:1 molecular ratio of rac-tramadol.hydrochloride and celecoxib) are described.

Expert opinion: CTC may provide a relevant addition to pain therapy due to its: i) unique co-crystal structure conferring differentiated intrinsic dissolution profiles on constituent APIs, ii) modified clinical pharmacokinetics (slower absorption of tramadol and faster absorption of celecoxib) compared with commercially available single-entity reference products (in agreement with modified dissolution rates), iii) superior benefit–risk ratio compared with reference products (suggested by preclinical synergistic antinociceptive effects, without potentiation of adverse effects), and iv) efficacy in a phase 2 trial of moderate to severe pain following extraction of ≥2 impacted third molars requiring bone removal, where CTC doses containing low doses of APIs exerted a significant effect. Phase 3 studies are currently ongoing.

KEYWORDS:

• Celecoxib
• co-crystal
• Co-Crystal of Tramadol-Celecoxib (CTC)
• efficacy
• pain
• pharmacokinetics
• safety
• tramadol

Article highlights

• Co-crystallisation of tramadol and celecoxib within CTC leads to modified clinical PK properties.

• These modifications lead to improved clinical efficacy and safety profiles of CTC compared with commercially available reference products alone or in free combination.

• CTC (100, 150 and 200 mg) exhibited improved analgesic efficacy compared with 100 mg tramadol

• CTC may therefore become a useful addition to the existing armamentarium against acute pain

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Acknowledgments

Medical writing support was provided by Hannah Mace CMPP at Aspire Scientific (UK).

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. All procedures performed in studies involving human participants were in accordance with the ethical standards of the relevant institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the clinical studies reported herein.

Declaration of interest

Clinical studies were funded by Mundipharma Research (UK) and Esteve Pharmaceuticals (Spain). N. Gascon, C. Almansa, M Merlos, JM Vela, G Encina, A Morte and CS Plata-Salamán are employed by Esteve Pharmaceuticals (Spain). K Smith is employed by Mundipharma Research (UK). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by Mundipharma Research (UK).